F. Chibon

Our research project at a glance

Our team seeks understanding the chromosomal mechanisms of pleomorphic sarcomas oncogenesis. These tumors, representing about half of sarcomas, or 2000 new cases per year in France, are very aggressive, do not currently benefit from effective systemic treatment and only surgery can, under conditions of appropriate management, achieve the patient remission.

Pleomorphic sarcomas are characterized by a very high chromosomal instability, their genome is very rearranged, consisting of numerous gains and losses of chromosomal fragments whose deciphering is made difficult by their number and lack of recurrence. If during the last 20 years, we have been able to identify some important actors of this oncogenesis (MDM2, CDK4, TP53, RB1, MYOCD1), to understand that the aggressiveness of these tumors is directly related to the level of this chromosomal instability, we still do not know the major drivers. In order to understand these mechanisms of oncogenesis, we now study these pleomorphic sarcomas according to two main axes:

the exhaustive study of all their genomic alterations by approaches of whole genome and transcriptome sequencing,

the study of cellular mechanisms and in particular tumor cell fusion that we have observed in these tumors.

Finally, our team being composed for half by clinicians (pathologists, medical oncologists, surgeons), results of our work are constantly envisaged in a context of transfer towards an improvement of the patients care and thus we develop tools allowing to optimize diagnosis and prognostication, in particular.

Objectives

The aim of our work is ultimately to provide a comprehensive understanding of the pleomorphic sarcomas oncogenesis, an essential step in establishing an efficient therapy.

Our objectives are then 3 orders:

1- Genetics: We lead, on behalf of the French Sarcoma Group, a project, within the framework of the ICGC (web), aiming to characterize and understand all the alterations (point mutations, structural variants, fusion genes, gains, losses) of leiomyosarcomas genome, pleomorphic sarcomas among the most frequent and aggressive. In this project, funded by ITMOCancer (INCA & INSERM) the entire genome and transcriptome of more than 200 leiomyosarcomas will be sequenced. We expect this project to provide us with keys about the genetic and biological mechanisms of leiomyosarcomas oncogenesis. Indeed, by identifying the altered genes, we will identify the biological pathways altered in this oncogenesis and by inferring the mutational process, we will know by what mechanisms this oncogenesis is triggered.Figure 1: CIRCOSplot: Circular representation of intra- (orange) and inter- (blue) chromosomal rearrangements detected in the genome of a LMS by Whole Genome Sequencing (WGseq)

2- Cellular: We are currently conducting a project supported by ARC and FRM to understand the impact of cancer cell fusion in sarcomas. It is indeed as a result of the fortuitous observation of this mechanism and its confirmation in vivo that we were interested in the diversion of this physiological cellular mechanism to drive oncogenesis. Thus we have been able to show that this fusion leads to a complete destabilization of the tumor genome, a reprogramming of the energetic metabolism and an increase of the tumor aggressiveness resulting in particular by the acquisition of the metastatic potential in vivo. We are now aiming to understand how this mechanism can act in the vey first steps of oncogenesis, how the destabilization of the genome takes place by studying the first post-fusion mitosis and how the capacity for metastatic dissemination following fusion is acquired ?

Right panel: 24-color painting of a chromosomal spreading from a hybrid cell in which new translocations are detected.

3- Translational: Transferring questions from the clinic to the laboratory and discoveries from the laboratory to the care of patients are among our objectives as well. Thus, after the identification and validation in recent years of a prognostic expression signature in sarcomas and other cancers, we are currently conducting a project to make this signature, which we have shown more relevant than the current tools, usable in pathology, for patients care. This is done through the development of a Nanostring approach, allowing the analysis of RNA extracted from FFPE samples, material available to pathologists to make their diagnosis in the daily practice.

The effective systemic therapies still lacking in sarcomas, we are also involved in clinical and preclinical research to evaluate new therapeutic approaches.